Sustained-release preparations of quinolone antibiotics and method for preparation thereof

ABSTRACT

The present invention relates to an orally administrable preparation comprising a quinolone antibiotic which releases the active compound with a delay.

[0001] The present invention relates to solid, orally administrablematrix preparations of quinolone antibiotics having delayed release andto a process for their preparation.

[0002] Active compounds from the quinolones class have been employed fora long time as broad-spectrum antibiotics, and numerous administrationforms are obtainable on the market, such as tablets, infusion solutions,eye drops etc.

[0003] For many medicaments—as also for the quinolonesclass-formulations are desirable which after administration once dailyguarantee a controlled, long-lasting and uniform release of the activecompound. In this way, the desired active compound concentration in theplasma (below: “plasma level”) and the therapeutic action can bemaintained over a relatively long period without large variations.Formulations which release the active compound in this manner over arelatively long period are designated as delayed-release orcontrolled-release (CR) preparations.

[0004] It is very difficult, however, to develop orally administrablequinolone preparations which, in spite of administration only oncedaily, guarantee an adequately high antibiotic action; the patient musttherefore take at least two doses daily. It is desirable, however, toreduce the frequency of taking of such quinolone antibiotics to oncedaily.

[0005] For the production of preparations having controlled release ofactive compound, in principle various techniques are known. Thus it isoften desired to leave the preparation for a relatively long period inthe stomach in order to make possible the rapid and complete absorptionof the active compound to be delayed in the absorption window (i.e. inthe section of the gastrointestinal tract in which absorption takesplace). The residence time in the stomach, however, depends strongly onthe nature and nutritive value of the food in the stomach (S. S. Davisin G. Hardy et al., Drug Delivery to the Gastrointestinal Tract, EllisHolwood Ltd., Chichester, England 1989). In order to prolong theresidence time in the stomach, various attempts have been investigatedwhich either

[0006] a) increase the density of the preparation (EP-A 265 061),

[0007] b) use special additives such as ammonium myristate which, as isknown, slow the further transport of preparations in thegastrointestinal tract (R. Gröning; G. Heung, Int. J. Pharm. 56, 111(1989)),

[0008] c) employ preparations swelling in the stomach (balloon tablets)(Agyilirah et al., Int. J. Pharm. 75, 241 (1991)),

[0009] d) employ preparations having a large spatial expansion (EP-A 235718) or

[0010] e) employ bioadhesive preparations which preferably should adhereto the mucous membranes of the gastrointestinal tract (R. Khosla, S. S.Davis, J. Pharm. Pharmacol. 39, 47 (1987)).

[0011] Another delayed-release technique makes use of a matrix ofhydrophilic polymers and, if appropriate, pharmaceutical excipients inwhich the active compound is embedded. In an aqueous environment, thepolymer swells to give a gel, which then either slowly erodes (togetherwith the poorly soluble active compound) or diffuses through the(readily soluble) active compound. The polymer can by hydrophilic,hydrophobic or mixed hydrophilic/hydrophobic. At present, matrix tabletsare very popular, since they are comparatively inexpensive and highlytolerable and can be produced in conventional equipment.

[0012] Another method consists in the use of buffered or pH-sensitivecoatings which allow controlled release in certain sections of thegastrointestinal tract.

[0013] A technically complicated method consists in the use of osmoticsystems (OROS) which function according to the following principle:water penetrates slowly into the tablet through a water-permeablemembrane and leads to swelling of a water-swellable ingredient there;the pressure resulting due to the increase in volume drives the activecompound out of the tablets through an opening intended for thispurpose.

[0014] All these techniques have disadvantages, in particular expensiveand complicated production methods, inter- and intraindividualvariability or dependence of the desired action on the posture.

[0015] In the production of delayed-release preparations, care also hasto be taken in each case of where the absorption of the active compoundcan take place: the smaller the absorption window, the more difficultthe production of delayed-release preparations turns out to be.Quinolones such as ciprofloxacin, for example, are mainly absorbed inthe upper part of the small intestine (duodenum); absorption in thelower part of the small intestine and in the large intestine issignificantly lower (S. Harder et al., Br. J. Clin. Pharmacol. 30,35-39, (1990)). Therefore the active compound must be released in orderto achieve maximum bioavailability before the preparation leaves thisabsorption window. Moreover, the strong influence of the pH of thesurrounding medium on the solubility of quinolone active compounds hasto be taken into account; it decreases with increasing pH.

[0016] The object of the invention was therefore to make availabledelayed-release preparations of quinolone antibiotics which guarantee anadequate therapeutic action on administration once daily.

[0017] The invention therefore relates to an orally administrableantibiotic matrix preparation comprising quinolone active compound,characterized in that it releases 80% of the active compound both in 0.1N hydrochloric acid and in acetate buffer at pH 4.5 in the USP XXIVpaddle test at 50 revolutions per minute/37° C. in the course of 1 to 4hours. In order to prevent floating up of the tablet during the test, itcan be placed in a wire cage, as is described, for example, in theJapanese Pharmacopoeia.

[0018] The term “quinolone active compound” in the context of thepresent invention denotes the class consisting of the substances havinga quinolone parent structure which can be used as antiinfectives, inparticular the quinolonecarboxylic acids. Preferred quinolone activecompounds include ciprofloxacin, olamufloxacin, clinafloxacin,trovafloxacin, cadrofloxacin, alatrofloxacin mesylate, gatifloxacin,rufloxacin, sparfloxacin, levofloxacin, irloxacin, grepafloxacin,moxifloxacin, prulifloxacin, pazufloxacin, gemifloxacin, sitafloxacin,tosulfloxacin, amifloxacin, lomefloxacin, R-lomefloxacin andnitrosoxacin-A. The most preferred quinolone active compound isciprofloxacin and its hydrates.

[0019] The term “quinolone active compound” in the context of thepresent invention also includes quinolone derivatives which only releasethe active compound in the body (‘prodrugs’), e.g. esters of aquinolonecarboxylic acid.

[0020] According to a preferred embodiment, the preparation according tothe invention contains as active compound a combination, preferably amixture, of two different quinolone derivatives. An example of such anembodiment according to the invention would be a preparation which asactive compound contains a mixture of two different quinolone salts.

[0021] A preferred embodiment relates to preparations which as activecompound contain the mixture of a free quinolone base and its salt.Mixtures of ciprofloxacin hydrochloride and ciprofloxacin betaine areparticularly preferred.

[0022] Ciprofloxacin hydrochloride is highly soluble, for example, atlow pH values; the solubility is significantly decreased, however, atthe pH of the intestinal tract (≧6.5). However, it has turned out thatmixtures of ciprofloxacin hydrochloride and free ciprofloxacin base(betaine) in a weight ratio of 1:20 to 20:1, in particular 1:10 to 10:1,are released from the preparation largely independently of pH (in the pHrange from 1 to 4.5). An equivalent effect can also be achieved by usingmixtures of other derivatives, e.g. salts, bases or prodrugs of theactive compound. Mixtures of stereoisomers in the context of theinvention do not come, however, under the term “combination of twodifferent quinolone derivatives”, but rather mixtures of hydrate andanhydrate.

[0023] A particular embodiment of the preparations according to theinvention relates to matrix tablets. Preferred matrix tablets contain adelayed-release part (CR part) and a rapid-release part (IR part).Suitable release-delaying polymers for the matrix are water-swellablepolymers, e.g. polysaccharides such as starches and starch derivatives(maize, wheat, rice and potato starch, carboxymethyl starches, sodiumstarch glycolates), cellulose ethers such as alkylcelluloses,hydroxyalkylcelluloses, carboxyalkylcelluloses and their alkali metalsalts (methyl-, hydroxymethyl-, hydroxyethyl-, hydroxypropyl- and sodiumcarboxymethylcelluloses, crosslinked carboxymethylcelluloses), dextrins,dextran, pectins, polyoses, gum arabic, tragacanth, carrageenan,galactommanans such as guar gum, algin, alginic acid and alginates,polypeptides and proteins such as gelatin and casein, furthermore chitinderivatives such as chitosan, fully synthetic polymers such as(meth)acrylic acid copolymers (methyl methacrylate, hydroxymethylmethacrylate copolymers, polyvinyl alcohol, uncrosslinkedpolyvinylpyrrolidone and vinylpyrrolidone copolymers, and mixtures ofthe compounds mentioned. Since the water-swellable polymers form gels inthe presence of water, they can also be called “gel-forming polymers”.

[0024] Highly viscous polymers are often used for delayed-releasepreparations. In the present invention, it has been found, however, thatlow-viscosity polymers positively effect the release behaviour of thepreparations. In principle, all hydrophilic polymers of low viscositycan be used for the purpose of delaying release. The term “lowviscosity”in the context of the present invention means an (apparent) viscosity of5 to 400 mPa·s (cP), preferably of at most 75 cP, in particular of atmost 50 cP, measured using a rotary viscometer as a 2% strength byweight aqueous solution at 20° C.

[0025] Hydroxypropylmethylcellulose (HPMC) is particularly preferred.HPMC of USP XXIV Specification 2910, i.e. having a methoxy content of 28to 30% by weight and a hydroxypropoxy content of 7 to 12% by weight,e.g. Metolose® 60 SH (Shinetsu, Japan) is especially preferred. Thedesired degree of delay of the preparation can be adjusted by choice ofviscosity and amount of HPMC.

[0026] Preferred HPMC has a viscosity of 5 to 400 cP, preferably of atmost 75 cP, in particular of at most 50 cP (in each case measured usinga rotary viscometer as a 2% strength by weight aqueous solution at 20°C.).

[0027] The content of the hydrophilic polymer, preferably of the HPMC,can vary within wide limits. Preferably, however, 1 part by weight ofhydrophilic polymer per 2 to 20, preferably per 5 to 15, parts by weightof active compound is employed.

[0028] In order to guarantee the release of the active compound from thedose form even in the small intestine and to keep the pH of the externallayer and the environment of the preparation in the acidic range andthereby to prevent as largely as possible the risk of the precipitationof the active compound in the higher pH of the intestinal fluid, anorganic acid can be incorporated into the preparation (if present,preferably in the delayed-release part); in this way, the activecompound is prepared in a form which is more accessible for absorption.For this purpose, preferred organic acids have 2 to 10 C atoms and 1 to4 carboxyl groups, for example acetic acid, malonic acid, succinic acid,fumaric acid, tartaric acid and citric acid.

[0029] Besides active compound, hydrophilic release-delaying polymerand, if appropriate, organic acid, the preparations according to theinvention can also contain disintegrants, e.g. crosslinkedpolyvinylpyrrolidone such as ®Kollidon CL, glidants, e.g. colloidalsilica such as ®Aerosil, hydrogenated vegetable oils, stearic acid, talcor mixtures thereof, lubricants, e.g. magnesium stearate, and also, ifappropriate, other excipients. Both glidants and lubricants arepreferably incorporated into the granules before the tabletting phase.

[0030] The tablets can then be coated in order, if appropriate, to maska bitter taste of the active compound, to protect the active compoundfrom the effect of light and/or in order to make the tabletsaesthetically more pleasing. The coating can be carried out, forexample, by spraying on an aqueous suspension of: film formers, e.g.HPMC, plasticizers, e.g. polyethylene glycol, and light-scattering andlight-absorbing pigments, e.g. titanium dioxide. To dry off the water,hot air can be directed at the tablet bed during the coating.

[0031] Delayed-release preparations can be prepared using the componentsdescribed. Besides the delayed-release part (CR part), a rapid-releasepart (IR part) can also be employed in order to obtain a rapid influxand a higher plasma level. Rapid-release (IR) preparations areunderstood in the context of the present invention as meaning thosewhich release the active compound according to USP XXIV paddle method asrapidly as desired, preferably within 3 minutes to less than 60 minutes.The rapid release can be controlled within certain limits by variationof the composition, e.g. by variation of the disintegrant content, or bythe production parameters. Rapid-release parts of the preparationaccording to the invention do not unconditionally have to contain twodifferent quinolone derivatives.

[0032] It is thus possible to produce combination preparations which ina single-unit dose form contain preparations having different releaseprofiles: thus preparations having a different release profile can beused in order to control the plasma level exactly timewise. “Combinationpreparations” within the meaning of the invention are understood asmeaning not only single-unit dose forms (‘fixed combinations’) andcombination packs, which separately of one another each contain apreparation having a different release profile (kit of parts), but alsoIR or CR parts which are administered simultaneously or at differenttimes, provided they are employed for the treatment or prophylaxis ofthe same disease.

[0033] The present invention thus also relates to a combinationpreparation which has a rapid-release part and a delayed-release part,e.g. in the form of a two-layer tablet. The rapid-release part cancontain quinolone active compound (e.g. ciprofloxacin hydrochloride andciprofloxacin betaine), disintegrant (e.g. crosslinkedpolyvinylpyrrolidone such as Kollidon® CL), glidants (colloidal silica,e.g. Aerosil®) and lubricants (e.g. magnesium stearate) and, ifappropriate, organic acid or other excipients. The delayed-release partscan contain active compound (ciprofloxacin hydrochloride andciprofloxacin betaine), the release-delaying polymer (e.g. HPMC of lowviscosity), organic acid (e.g. succinic acid), a glidant (e.g. colloidalsilica) and a lubricant (e.g. magnesium stearate) and, if appropriate,further excipients. The starting materials for the rapid-release and thedelayed-release part can be granulated before tabletting (e.g. using wetor dry granulation techniques). The granules can be mixed with glidantsand lubricants, and the compressible (ready-to-compress) granules of thetwo layers can be tabletted (e.g. with the use of conventional two-layertabletting machines) to give two-layer tablets. Some of the glidantcould also be granulated.

[0034] Since the addition of an organic acid increases the release rateof the active compound, in particular of ciprofloxacin hydrochloride andbetaine, it may also be recommended to admix organic acid to the IRpart.

[0035] The delayed-release preparations according to the inventionexpediently contain 500 to 1000 mg of active compound, calculated asbetaine, per single-unit dose form. “Single-unit dose forms” areunderstood as meaning those preparations which are administered as anindividual dose, e.g. tablets, coated tablets or capsules.

[0036] For the production of delayed-release preparations according tothe invention having an IR and CR part, it is possible to use, forexample, the following process: for the production of the IR part theactive compound (preferably as a mixture of two derivatives) is mixedwith disintegrant, in particular Kollidon CL, and granulated and mixedwith glidant, in particular aerosol, and lubricant, in particularmagnesium stearate, in order to obtain compactable (ready-to-compress)IR granules.

[0037] For the delayed-release part, the active compound (as a mixtureof two derivatives) is mixed with acid, e.g. succinic acid, andgel-forming polymer, in particular HPMC, and granulated. These CRgranules are mixed with glidant, in particular Aerosil®, and lubricant,in particular magnesium stearate, in order to obtain compressible(ready-to-compress) CR granules. The (ready-to-compress) CR granules andthe IR granules are tabletted using a conventional two-layer tablettingmachine to give a two-layer tablet. The tablet obtained can then becoated.

[0038] The following working examples are intended to explain thesubject of the invention with the aid of two-layer tablets, but withoutrestricting it thereto.

EXAMPLES Example 1

[0039] Amount in mg Substances employed 366.70 Ciprofloxacinhydrochloride 41.70 Ciprofloxacin betaine 46.700 Kollidon CL** 4.30Aerosil 200*** 4.70 Magnesium stearate 464.10 Subtotal IR part 302.70Ciprofloxacin hydrochloride 464.30 Ciprofloxacin betaine 125.40 Succinicacid 103.10 Hydroxypropylmethylcellulose 50 cP* 5.20 Aerosil 200*** 9.30Magnesium stearate 1 010.00 Subtotal CR part 18.00Hydroxypropylmethylcellulose 15 cP* 6.00 Titanium dioxide 6.00Polyethylene glycol 400**** 30.00 Coating sub-total 23 × 9.5 mm Oblongtablet

Example 2

[0040] Amount in mg Substances employed 183.40 Ciprofloxacinhydrochloride 20.90 Ciprofloxacin betaine 22.30 Kollidon CL 2.30Magnesium stearate 1.10 Aerosil 200 230.00 Subtotal IR part 151.40Ciprofloxacin hydrochloride 232.10 Ciprofloxacin betaine 64.00 Succinicacid 52.30 Hydroxypropylmethylcellulose 15 cP 7.60 Magnesium stearate2.60 Aerosil 200 510.00 Subtotal CR part 12.00Hydroxypropylmethylcellulose 15 cP 4.00 Polyethylene glycol 400 4.00Titanium dioxide 20.00 Coating sub-total 19 × 8 mm Oblong tablet

Example 3

[0041] Amount in mg Substances employed 183.40 Ciprofloxacinhydrochloride 20.90 Ciprofloxacin betaine 22.30 Kollidon CL 2.30Magnesium stearate 1.10 Aerosil 200 230.00 Subtotal IR part 151.40Ciprofloxacin hydrochloride 232.10 Ciprofloxacin betaine 65.10 Succinicacid 73.00 Hydroxypropylmethylcellulose 15 cP 10.70 Magnesium stearate2.70 Aerosil 200 535.00 Subtotal CR part 12.00Hydroxypropylmethylcellulose 15 cP 4.00 Polyethylene glycol 3350 4.00Titanium dioxide 20.00 Coating sub-total 19 × 8 mm Oblong tablet

Example 4

[0042] Amount in mg Substances employed 183.40 Ciprofloxacinhydrochloride 20.90 Ciprofloxacin betaine 22.30 Kollidon CL 2.30Magnesium stearate 1.10 Aerosil 200 230.00 Subtotal IR part 151.40Ciprofloxacin hydrochloride 232.10 Ciprofloxacin betaine 64.00 Succinicacid 72.00 Hydroxypropylmethylcellulose 50 cP 7.90 Magnesium stearate2.60 Aerosil 200 530.00 Subtotal CR part 12.00Hydroxypropylmethylcellulose 15 cP 4.00 Polyethylene glycol 400 4.00Titanium dioxide 20.00 Coating sub-total 19 × 8 mm Oblong tablet

Example 5

[0043] Amount in mg Substances employed 262.00 Ciprofloxacinhydrochloride 29.80 Ciprofloxacin betaine 8.90 Succinic acid 42.20Kollidon CL 1.80 Aerosil 200 5.30 Magnesium stearate 350.00 Subtotal IRpart 116.40 Ciprofloxacin hydrochloride 178.50 Ciprofloxacin betaine134.00 Succinic acid 87.80 Hydroxypropylmethylcellulose 15 cP 2.70Aerosil 200 10.60 Magnesium stearate 530.00 Subtotal CR part 12.00Hydroxypropylmethylcellulose 15 cP 4.00 Polyethylene glycol 400 4.00Titanium dioxide 20.00 Coating sub-total 19 × 8 mm Oblong tablet

Example 6

[0044] Amount in mg Substances employed 183.40 Ciprofloxacinhydrochloride 20.90 Ciprofloxacin betaine 6.20 Succinic acid 24.70Kollidon CL 1.20 Aerosil 200 3.60 Magnesium stearate 240.00 Subtotal IRpart 151.40 Ciprofloxacin hydrochloride 232.10 Ciprofloxacin betaine174.00 Succinic acid 95.70 Hydroxypropylmethylcellulose 15 cP 3.40Aerosil 200 13.40 Magnesium stearate 670.00 Subtotal CR part 12.00Hydroxypropylmethylcellulose 15 cP 4.00 Polyethylene glycol 400 4.00Titanium dioxide 20.00 Coating sub-total 19 × 8 mm Oblong tablet

Example 7

[0045] Amount in mg Substances employed 366.70 Ciprofloxacinhydrochloride 41.70 Ciprofloxacin betaine 46.60 Kollidon CL 4.70Magnesium stearate 2.30 Aerosil 200 462.00 Subtotal IR part 302.70Ciprofloxacin hydrochloride 464.30 Ciprofloxacin betaine 125.30 Succinicacid 103.00 Hydroxypropylmethylcellulose 15 cP 20.50 Magnesium stearate5.20 Aerosil 200 1 021.00 Subtotal CR part 18.00Hydroxypropylmethylcellulose 15 cP 6.00 Polyethylene glycol 3350 6.00Titanium dioxide 30.00 Coating sub-total 23 × 9.5 mm Oblong tablet

Comparative Example A

[0046] Amount in mg Substances employed 357.00 Ciprofloxacin betaine58.00 Kollidon CL 6.00 Magnesium stearate 4.00 Aerosil 200 425.00Subtotal IR part 833.00 Ciprofloxacin betaine 108.00 Succinic acid108.00 Hydroxypropylmethylcellulose 50 cP 16.00 Magnesium stearate 10.00Aerosil 200 1 075.00 Subtotal CR part 18.00 Hydroxypropylmethylcellulose15 cP 6.00 Polyethylene glycol 400 6.00 Titanium dioxide 30.00 Coatingsub-total 23 × 9.5 mm Oblong tablet

Comparative Example B

[0047] Amount in mg Substances employed 357.00 Ciprofloxacin betaine58.00 Kollidon CL 6.00 Magnesium stearate 4.00 Aerosil 200 425.00Subtotal IR part 833.00 Ciprofloxacin betaine 108.00 Succinic acid108.00 Hydroxypropylmethylcellulose 3 cP 16.00 Magnesium stearate 10.00Aerosil 200 1 075.00 Subtotal CR part 18.00 Hydroxypropylmethylcellulose15 cP 6.00 Polyethylene glycol 400 6.00 Titanium dioxide 30.00 Coatingsub-total 23 × 9.5 mm Oblong tablet

[0048] In 0.1N HCl solution or acetate buffer at pH 4.5, thepreparations according to the invention of Examples 1 to 7 show largelypH-independent release in conventional release apparatuses (USP paddletest), while the preparations of Comparative Examples A and B showstrong pH dependence.

1. Orally administrable antibiotic matrix preparation comprisingquinolone active compound, characterized in that it releases 80% of theactive compound both in 0.1 N hydrochloric acid and in acetate buffer atpH 4.5 in the USP XXIV paddle test at 50 revolutions per minute/37° C.in the course of 1 to 4 hours.
 2. Orally administrable preparationcomprising a quinolone antibiotic, characterized in that it contains amixture of a) gel-forming polymer of a viscosity of 5 to 400 cP,measured as a 2% strength by weight aqueous solution at 20° C., and b) amixture of at least two derivatives of the quinolone antibiotic. 3.Orally administrable preparation comprising a quinolone antibiotic,characterized in that it contains a mixture of a) water-swellablepolymer and b) a mixture of at least two derivatives of the quinoloneantibiotic.
 4. Preparation according to claims 1 to 3, characterized inthat it contains, as a mixture of two derivatives of the quinoloneantibiotic, a mixture of a salt with the free base.
 5. Preparationaccording to claims 1 to 4, characterized in that it contains, as amixture of two derivatives of the quinolone antibiotic, a mixture of twosalts.
 6. Preparation according to claims 1 to 5, characterized in thatthe quinolone antibiotic is ciprofloxacin.
 7. Preparation according toclaims 1 to 6, characterized in that the two derivatives areciprofloxacin hydrochloride and ciprofloxacin betaine.
 8. Preparationaccording to claims 1 to 7, characterized in that the gel-formingpolymer is hydroxypropylmethylcellulose of a viscosity of at most 75 cP,measured as a 2% strength by weight aqueous solution at 20° C. 9.Preparation according to claims 1 to 8, characterized in that thehydroxypropylmethylcellulose has a viscosity of at most 50 cP, measuredas a 2% strength by weight aqueous solution at 20° C.
 10. Preparationaccording to claims 1 to 9, characterized in that the preparation is acombination preparation comprising a rapid-release (IR) part and adelayed release (CR) part.
 11. Preparation according to claims 1 to 10,characterized in that it contains 2 to 20 parts by weight of activecompound mixture per part by weight of hydroxypropylmethylcellulose. 12.Process for the production of a preparation according to claims 1 to 11,according to which one part of the active compound is mixed withdisintegrant, granulated and mixed with glidant and lubricant (IR part),and another part of the active compound is mixed with acid andhydroxypropylmethylcellulose, granulated and mixed with glidant andlubricant (CR part), and IR part and CR part are tabletted to givecombination tablets and the resulting tablets are coated.